Miami Beach, Florida
December 4th, 1998 (12:50pm - 2:45pm)
Introduction.There are several HLA and clinical outcome studies currently on-going through the NMDP. The purpose of the 13th International Histocompatability Workshop is not to duplicate the work of the NMDP. The purpose of the workshop is to address questions we feel can only be addressed on an international scale by pooling our resources.
Summary of the JMDP study (450 transplants, 140 for CML), in comparison with the FHCRC (300 CML transplants) study: FHCRC shows no appreciable affect of HLA-A mismatching on GVHD. Japanese show a large effect on GVHD if there is an HLA-A allele mismatch. The specific HLA-A allele mismatches are non-overlapping between the two studies. We hypothesize that the nature of the HLA differences may play a role in defining transplant risks. By looking at a worldwide set of data that contains different allele mismatches we can examine the effect of specific epitope mismatching by codon and position. HLA-A2 is an excellent candidate to investigate because of its high frequency worldwide (other candidates are B15 and DR4). From this data, we also hypothesize that polymorphisms other than those of classical HLA class I and II may contribute to clinical outcome.
Hypothesis 1: Different HLA-A allele mismatches confer different risks to mortality after unrelated stem cell transplantation for CML
Hypothesis 2: Single nucleotide polymorphisms (SNPs) encoded in the MHC Class I region are biologically relevant. (Joint effort with Dr. Dan Geraghty and development of oligonucleotide ligation assays for SNPs identification).
Priorities for June 2001:
1. CML unrelated stem cell transplants
2. HLA-A2
3. SNPs- Class I
We have many laboratories on board for high resolution typing. Working group meetings in Vancouver and Heidelberg focused on HLA issues. What today's Working Group meeting should focus on is to identify CML transplants and assemble database of clinical variables. We would like to propose that we study CMLs because of the homogeneous nature of this population. If we require a second level of focus due to volume of typing, we would propose looking at those CMLs that are HLA-A2 positive.
We would characterize all transplants for HLA-A, B, C, DRB1, DQB1 and DPB1 alleles. For HLA-A* 0201-positive pairs, HA-1 typing will be necessary. All transplants will be analyzed for SNPs.
Discussion of How Best to Identify CML Transplants. There were 4 major suggestions on how to identify CML transplants:
1. Start with the transplant centers; send IDs of transplants having complete outcome data to labs to find samples.
2. Start with the registries; send IDs of transplants having complete outcome data to labs to find samples.
3. Repositories provide IDs of complete pairs having DNA to transplant centers/registries.
4. HLA labs identify pairs having DNA and send Ids to transplant centers/registries.
For the NMDP, starting with either the Irwin repository or with the clinical database are equivalent.
For IBMTR/EBMT, lists of CML transplants can be sent to transplant centers requesting information on availability of DNA and laboratory contact.
To Do: Create IBMTR/EBMT survey for transplant centers and labs to locate DNA.Clinical Endpoints. In addition to survival, the working group is interested in collecting GVHD data. IBMTR/EBMT "TED" form is adopted as a uniform GVHD reporting scheme internationally. The plan is for IHWC database to create fields to accommodate IBMTR/EBMT "TED" form.
Supportive Care. Collecting CMV serostatus on donor and recipient is straightforward, however use of gancyclovir will be difficult to interpret. It will also be difficult to interpret and correct for other antimicrobials and other supportive measures since they differ from center to center.
To Do: Form a Clinical Working Group of members to review clinical data needed:Members: Mary Horowitz, Janet Hegland, Andrea Bacigalupo, Jan Cornelissen, Hans Messner, Effie Petersdorf
Power Calculations. We estimate that 5000 CML transplants are needed for the June 2001 analysis. Currently 3000 CML transplants have been performed through NMDP, and 1200-2000 are anticipated in 1999-2000. Additionally, 1000 could be expected from other registries.
Haploidical Related Mismatched Transplants.IBMTR can include data on haploidentical related transplants in their survey. The working group will aim to include as many of these transplants as possible in 2001 analysis.
HLA Genotypically Identical Sibling Transplants. HLA genotypically identical sibling transplants will be used as a comparison group. Transplant centers will need to help identify and contribute clinical data.
To Do: Survey transplant centers for matched sibling transplants for CML. Provide mechanism for centers to translate data with IHWC informatics.Timeline
1. Immediate - hold conference call to determine what clinical data we need
2. Labs are ready to begin. Start doing work in January 1999. (Some regions have obtained grant funding to do this work and are ready to go.)
3. Interim check in June 2000
4. December 2000 - second check
5. Working group should be given raw data to do analysis well before Whistler. Most testing should be done by Jan-Feb 2001
6. Convene June 2001
7. Workshop reports and conference symposia, June 2001
8. Workshop proceedings
9. Subsequent publications
Participant in Workshop Studies
1. Laboratories
2. Transplant Centers
3. Registries
Proposal from Dr. Ben Bradley, Bristol, UK - presented by Dr. Jill Hows:
Dr. Hows will speak to Dr. Bradley to simplify the proposal. Copies of the current proposal were handed out to those present. This will also be placed on the website once Seattle receives it. Comments should go directly to Dr. Bradley (cc. Dr. Petersdorf.)
Proposal from Dr. Francesco Dazzi, Hammersmith, UK:
Measurement of in vitro Allo-Response for the Selection of Unrelated Donors.
Multicenter study of HTL frequency in URD transplant pairs.
Plan:
CP-CML patients (homogeneous APC)
3 pairs to confirm variability/reliability
End-point=~20 pairs/center (5-6 centers)
Methods:
T-Cell enriched Donor Cell prep (CD14, CD19, CD33, CD56)
FACS analysis R/S
Measurement of IL2, g1FN, IL5
Recommendations: IHWC to provide Dr. Dazzi and Dr. Lechler with a list of Workshop participants so that they can coordinate this project directly with labs. This is necessary because the genomic analysis will not collect fresh cells from transplants.
